Epidemiology and Clinical Outcomes of Patients with Acute Hypoxaemic Respiratory Failure Admitted to Australian and New Zealand Intensive Care Units

Statistical Analysis

Author

Dr Benjamin Moran, MBBS, BMedSci (Hons), MMedStats, FCICM, FANZCA

Published

June 6, 2024

1 Introduction

This is an explanation of the statistical analysis for the study examining the epidemiology and outcomes of patients admitted to ICU with acute hypoxaemic respiratory failure (AHRF).

2 Methods

This is a retrospective study using data from the Australian and New Zealand Intensive Care Society (ANZICS) adult ICU patient database (APD). This manuscript has been prepared and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement.

2.1 Patient Population

We included all patients in the ANZICS APD from 01/01/2005 to 31/12/2022. Patients were categorised into PF ratio subgroups according to the severity definitions below.

2.2 Aims and Objectives

  1. Determine the association between PaO2:FiO2 ratio and hospital mortality.
  2. Determine the hospital mortality trends over time across PaO2:FiO2 ratio categories.
  3. Determine the admissions to ICU with AHRF over time across PaO2:FiO2 ratio categories.
  4. Determine the trends in proportion of hospital outcomes (Hospital mortality, ICU mortality, ICU length of stay, hospital length of stay, discharge home, nursing home/palliation, rehabilitation, other acute care hospital, other hospital ICU) over time by AHRF categories.
  5. Determine the association between PaO2:FiO2 ratio and hospital mortality in pre-specified subgroups (Level of ventilatory support, gender, age categories, country, hospital type, admission diagnosis, presence of treatment limitations at ICU admission)
  6. Determine the time to death of each AHRF categories.
  7. Determine the time to death of time categories.

2.3 Definition of Acute Hypoxaemic Respiratory Failure

Currently, there is heterogeneity in the precise definition of Acute Hypoxaemic Respiratory Failure (AHRF). For this study, we have defined AHRF as a PaO2:FiO2 ratio < 300 mmHg. AHRF can further be categorised as mild (PaO2:FiO2 200-300 mmHg), moderate (PaO2:FiO2 100-200 mmHg) and severe (PaO2:FiO2 <100 mmHg). Further categorsiation can be made into moderate-severe (PaO2:FiO2 100-150 mmHg).

2.4 Statistical Analysis

Baseline ICU- and patient-level characteristics and unadjusted outcomes were summarized using standard descriptive statistics. Continuous variables were reported as either means with standard deviation or medians and interquartile range, and categorical variables reported as number and percentages.

2.4.1 Covariate Selection for Multivariable Regression Models for Adjusted Outcomes

A directed acyclic graph (DAG) was used to generate a minimum adjustment set of covariates for the causal pathway from AHRF to hospital outcomes. Covariates were selected based on potential mechanistic associations with other variables. In addition to this, variables were selected if they increased the precision of the estimate. All back-door paths were closed and a minumum adjustment set of selected variables were used for that particular model. For all outcomes, baseline variables that were included in the model included PaO2:FiO2 ratio, chronic respiratory disease, chronic cardiovascular disease, frailty, smoking intensity and severity of illness scores.

2.4.2 Model Fitting

To analyse the association of AHRF and hospital outcomes, a multivariable, hierarchical logistic regression model was used with patients nested within sites and site treated as a random effect. Predicted probabilities were generated from the model output and displayed graphically as the effect on hospital outcomes by either the continuous PaO2:FiO2 ratio or time. The association between either PaO2:FiO2 ratio or time and hospital outcomes was modeled using restricted cubic splines with 4 knots to allow for non-linear association. Changes over time were described with the estimand of Absolute Risk Reduction (with 95% CI). To determine whether changes over time differed between different AHRF categories, an interaction term between time and the AHRF categories was fitted.

2.4.3 Time-to-Event Analysis

Time to death was analysed using Cox-proportional hazards regression with random effects (frailty model), with covariates included as determined by the minimum adjustment set from the previously constructed DAG. The results are presented as a Kaplan-Meier curve generated from the Cox Proportional Hazards regression with the HR (95% CI) for each AHRF category compared to no AHRF (“None” category). To further investigate the change over time, the study period was divided into 3 cohorts (2005-09, 2010-14, 2015-19, 2020-2022). These were presented as Kaplan-Meier curves from the Cox regression, with the HR (95% CI) comparing each time epoch to the initial time (2005-09). Each AHRF category is displayed as a separate Kaplan-Meier curve to examine the change within that category over time.

As there were >1,500,000 patients in the dataset, a 2-sided p-value of 0.001 was used for statistical significance. Given that there is an increased risk of Type-1 error with multiple testing, the results of the secondary objectives should be viewed as exploratory. Hence, no adjustment for multiplicity was used. Only patients with complete data for all covariates were included in the analysis. Statistical analyses were performed using R Version 4.3.1 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) and RStudio Version 2023.06.1 (Posit Software, PBC, Boston, MA). Packages used for analysis included tidyverse, data.table, gtsummary, lme4, survival and ggsurvfit.

2.5 Subgroup Analysis

Patients were analysed for the association of PF ratio and in-hospital mortality in the following subgroups: Receiving invasive ventilation on day 1, receiving invasive ventilation at any time during the ICU admission, receiving ECMO during the ICU admission, levels of ventilatory support (none, non-invasive ventilation, invasive ventilation, extra-corporeal membrane oxygenation), gender, age categories, admission diagnosis (medical, surgical, cardiac, neurosurgery/trauma, COVID pneumonitis), and treatment limitation status on ICU admission.

2.6 Sensitivity Analysis

Post-hoc sensitivity analyses were performed on the pre-specified variables of severity of illness scores, and for duration of invasive ventilation. In the first sensitivity analysis, modelling was repeated substituting the APACHE III score for APACHE II, ANZROD and SOFA scores. In the second sensitivity analysis, modelling was repeated on the pre-specified variables of invasive ventilation of more than 12 hours.

3 Results

Of 1,560,221 patients admitted to 211 ICUs during the study period, 826,106 (52.9%) patients had acute hypoaxemic respiratory failure. Of this cohort, 424382 (27.2%) had mild AHRF, 324,630 (20.8%) had moderate AHRF and 77,094 (4.9%) had severe AHRF.

3.1 Patient Demographics

Below are the demographic tables. This table has the 4 AHRF categories (none, mild, moderate, severe) to look at the breakdown of patients within each AHRF category.

Characteristic Overall1 Acute Hypoxaemic Respiratory Failure
No (PF >300)1 Yes (PF <300)1
Number of Patients 1,560,221 734,115 826,106
Median Age in Years (IQR) 66 (53-75) 65 (49-75) 67 (55-76)
Age Category, Years


    <44 241,138 (15%) 141,470 (19%) 99,668 (12%)
    >84 112,518 (7.2%) 54,908 (7.5%) 57,610 (7.0%)
    45-64 474,408 (30%) 217,225 (30%) 257,183 (31%)
    65-84 729,623 (47%) 319,327 (44%) 410,296 (50%)
Gender


    Female 641,352 (41%) 326,027 (44%) 315,325 (38%)
    Male 918,260 (59%) 407,783 (56%) 510,477 (62%)
    Intersex/Indeterminate 390 (<0.1%) 205 (<0.1%) 185 (<0.1%)
    Unknown 219 (<0.1%) 100 (<0.1%) 119 (<0.1%)
Median APACHE II Score (IQR) 15 (11-21) 14 (10-18) 17 (13-23)
Median APACHE III Score (IQR) 52 (39-68) 47 (35-61) 56 (43-74)
Median ANZROD (IQR) 0.09 (0.18) 0.06 (0.13) 0.12 (0.21)
Median SOFA (IQR) 4 (2-6) 3 (1-4) 5 (3-7)
Admission Diagnosis


    Medical 478,338 (31%) 176,685 (25%) 301,653 (37%)
    Post-Operative 432,367 (28%) 243,005 (34%) 189,362 (23%)
    Sepsis 113,516 (7.5%) 47,693 (6.7%) 65,823 (8.2%)
    Trauma/Neurosurgery 164,707 (11%) 105,030 (15%) 59,677 (7.4%)
    Cardiac Surgery 330,028 (22%) 139,524 (20%) 190,504 (24%)
COVID Penumonitis (Proven) 4,451 (0.3%) 249 (<0.1%) 4,202 (0.5%)
Admission Source


    Emergency Department 379,997 (24%) 159,769 (22%) 220,228 (27%)
    Operating Theatre/Recovery 897,931 (58%) 474,998 (65%) 422,933 (51%)
    Ward 188,779 (12%) 61,825 (8.4%) 126,954 (15%)
    ICU, Same Hospital 2,088 (0.1%) 769 (0.1%) 1,319 (0.2%)
    Other Hospital 90,715 (5.8%) 36,435 (5.0%) 54,280 (6.6%)
    Direct from Home 711 (<0.1%) 319 (<0.1%) 392 (<0.1%)
Hospital Type


    Tertiary 738,248 (47%) 339,133 (46%) 399,115 (48%)
    Metropolitan 243,919 (16%) 99,911 (14%) 144,008 (17%)
    Rural / Regional 145,760 (9.3%) 58,204 (7.9%) 87,556 (11%)
    Private 432,294 (28%) 236,867 (32%) 195,427 (24%)
Invasive MV 294,060 (46%) 113,665 (37%) 180,395 (54%)
IMV Day 1


    1 272,472 (17%) 105,681 (14%) 166,791 (20%)
    2 444,137 (28%) 246,042 (34%) 198,095 (24%)
    NULL 843,612 (54%) 382,392 (52%) 461,220 (56%)
NIV 74,382 (13%) 13,723 (4.9%) 60,659 (20%)
ECMO 1,630 (0.3%) 257 (<0.1%) 1,373 (0.5%)
Tracheostomy


    1 8,962 (0.6%) 3,072 (0.4%) 5,890 (0.7%)
    2 553,685 (35%) 274,161 (37%) 279,524 (34%)
    NULL 997,574 (64%) 456,882 (62%) 540,692 (65%)
1 n; Median (25%-75%); n (%); Mean (SD)
Characteristic Overall1 Acute Hypoxaemic Respiratory Failure Category
None (PF >300)1 Mild (PF 200-300)1 Moderate (PF 100-200)1 Severe (PF < 100)1
Number of Patients 1,560,221 734,115 424,382 324,630 77,094
Median Age in Years (IQR) 66 (53-75) 65 (49-75) 67 (56-76) 66 (55-75) 65 (52-75)
Age Category, Years




    <44 241,138 (15%) 141,470 (19%) 47,537 (11%) 39,964 (12%) 12,167 (16%)
    >84 112,518 (7.2%) 54,908 (7.5%) 31,478 (7.4%) 21,151 (6.5%) 4,981 (6.5%)
    45-64 474,408 (30%) 217,225 (30%) 130,078 (31%) 102,607 (32%) 24,498 (32%)
    65-84 729,623 (47%) 319,327 (44%) 214,624 (51%) 160,349 (49%) 35,323 (46%)
Gender




    Female 641,352 (41%) 326,027 (44%) 164,252 (39%) 122,366 (38%) 28,707 (37%)
    Male 918,260 (59%) 407,783 (56%) 259,945 (61%) 202,173 (62%) 48,359 (63%)
    Intersex/Indeterminate 390 (<0.1%) 205 (<0.1%) 112 (<0.1%) 54 (<0.1%) 19 (<0.1%)
    Unknown 219 (<0.1%) 100 (<0.1%) 73 (<0.1%) 37 (<0.1%) 9 (<0.1%)
Median APACHE II Score (IQR) 15 (11-21) 14 (10-18) 15 (12-20) 18 (14-24) 23 (18-31)
Median APACHE III Score (IQR) 52 (39-68) 47 (35-61) 52 (40-67) 60 (46-78) 76 (58-102)
Median ANZROD (IQR) 0.09 (0.18) 0.06 (0.13) 0.08 (0.16) 0.14 (0.21) 0.27 (0.29)
Median SOFA (IQR) 4 (2-6) 3 (1-4) 4 (3-6) 5 (4-7) 7 (5-10)
Admission Diagnosis




    Medical 478,338 (31%) 176,685 (25%) 120,753 (29%) 136,715 (43%) 44,185 (59%)
    Post-Operative 432,367 (28%) 243,005 (34%) 121,506 (29%) 59,472 (19%) 8,384 (11%)
    Sepsis 113,516 (7.5%) 47,693 (6.7%) 30,512 (7.4%) 27,028 (8.5%) 8,283 (11%)
    Trauma/Neurosurgery 164,707 (11%) 105,030 (15%) 38,829 (9.4%) 18,023 (5.7%) 2,825 (3.8%)
    Cardiac Surgery 330,028 (22%) 139,524 (20%) 102,972 (25%) 76,061 (24%) 11,471 (15%)
COVID Penumonitis (Proven) 4,451 (0.3%) 249 (<0.1%) 600 (0.1%) 2,340 (0.7%) 1,262 (1.6%)
Admission Source




    Emergency Department 379,997 (24%) 159,769 (22%) 97,029 (23%) 95,474 (29%) 27,725 (36%)
    Operating Theatre/Recovery 897,931 (58%) 474,998 (65%) 254,818 (60%) 146,535 (45%) 21,580 (28%)
    Ward 188,779 (12%) 61,825 (8.4%) 48,189 (11%) 58,167 (18%) 20,598 (27%)
    ICU, Same Hospital 2,088 (0.1%) 769 (0.1%) 582 (0.1%) 543 (0.2%) 194 (0.3%)
    Other Hospital 90,715 (5.8%) 36,435 (5.0%) 23,587 (5.6%) 23,743 (7.3%) 6,950 (9.0%)
    Direct from Home 711 (<0.1%) 319 (<0.1%) 177 (<0.1%) 168 (<0.1%) 47 (<0.1%)
Hospital Type




    Tertiary 738,248 (47%) 339,133 (46%) 200,430 (47%) 160,733 (50%) 37,952 (49%)
    Metropolitan 243,919 (16%) 99,911 (14%) 65,054 (15%) 60,547 (19%) 18,407 (24%)
    Rural / Regional 145,760 (9.3%) 58,204 (7.9%) 39,893 (9.4%) 37,813 (12%) 9,850 (13%)
    Private 432,294 (28%) 236,867 (32%) 119,005 (28%) 65,537 (20%) 10,885 (14%)
Chronic Respiratory Disease 113,366 (7.3%) 32,308 (4.4%) 36,569 (8.6%) 36,332 (11%) 8,157 (11%)
Chronic CVS Disease 141,997 (9.1%) 57,711 (7.9%) 41,613 (9.8%) 34,425 (11%) 8,248 (11%)
Chronic Hepatic Disease 28,451 (1.8%) 11,995 (1.6%) 7,628 (1.8%) 6,821 (2.1%) 2,007 (2.6%)
Chronic Renal Disease 51,172 (3.3%) 22,705 (3.1%) 14,034 (3.3%) 11,420 (3.5%) 3,013 (3.9%)
Frailty




    Fit/Well 279,102 (59%) 148,491 (64%) 73,055 (57%) 48,012 (54%) 9,544 (51%)
    Mild 141,890 (30%) 64,823 (28%) 40,847 (32%) 29,900 (33%) 6,320 (34%)
    Moderate 34,859 (7.4%) 14,260 (6.1%) 10,321 (8.1%) 8,400 (9.4%) 1,878 (10%)
    Severe 13,361 (2.8%) 5,151 (2.2%) 3,976 (3.1%) 3,413 (3.8%) 821 (4.4%)
Diabetes




    None 394,910 (73%) 202,650 (76%) 105,305 (71%) 71,654 (69%) 15,301 (71%)
    Type-1 Diabetes 13,832 (2.6%) 7,974 (3.0%) 3,185 (2.2%) 2,214 (2.1%) 459 (2.1%)
    Type-2 Diabetes 125,514 (23%) 53,514 (20%) 37,893 (26%) 28,423 (28%) 5,684 (26%)
    Gestational Diabetes 1,695 (0.3%) 1,087 (0.4%) 349 (0.2%) 213 (0.2%) 46 (0.2%)
    Secondary Diabetes/Other 3,595 (0.7%) 1,677 (0.6%) 1,029 (0.7%) 738 (0.7%) 151 (0.7%)
1 n; Median (25%-75%); n (%); Mean (SD)

3.2 Admission Diagnoses

Below are the admission diagnoses and the associated AHRF categories, ordered by the most common.

Characteristic Overall1 Acute Hypoxaemic Respiratory Failure Category
None (PF >300)1 Mild (PF 200-300)1 Moderate (PF 100-200)1 Severe (PF < 100)1
Number of Patients 1,560,221 734,115 424,382 324,630 77,094
Cause of AHRF




    Cardiac Surgery 330,028 (22%) 139,524 (20%) 102,972 (25%) 76,061 (24%) 11,471 (15%)
    Respiratory Disease 150,592 (9.9%) 24,239 (3.4%) 40,901 (9.9%) 64,270 (20%) 21,182 (28%)
    Cardiovascular Disease 114,115 (7.5%) 37,821 (5.3%) 29,509 (7.1%) 33,109 (10%) 13,676 (18%)
    Sepsis 113,516 (7.5%) 47,693 (6.7%) 30,512 (7.4%) 27,028 (8.5%) 8,283 (11%)
    Gastrointestinal Surgery 215,730 (14%) 115,486 (16%) 62,693 (15%) 32,861 (10%) 4,690 (6.2%)
    Other Non-Operative 247,942 (16%) 131,470 (18%) 59,651 (14%) 46,174 (15%) 10,647 (14%)
    Other Post-Operative 347,033 (23%) 215,704 (30%) 88,334 (21%) 37,796 (12%) 5,199 (6.9%)
COVID Pneumonitis 4,451 (0.3%) 249 (<0.1%) 600 (0.1%) 2,340 (0.7%) 1,262 (1.6%)
1 n; n (%)

3.3 Admission Diagnoses Over Time

Below are the admission diagnoses trends over time, with categorisation by AHRF severity.

3.4 Admissions to ICU with AHRF Over Time

The proportion of AHRF admissions to ICU was 53.6% (559/1,042) in 2005 and 52.0% (66521/127,934) in 2022. The proportion of patients admitted with mild AHRF to ICU was 27.2% (283/1,042) in 2005 and 27.6% (35,306/127,934) in 2022. The proportion of patients admitted with moderate AHRF to ICU was 20.6% (215/1,042) in 2005 and 19.9% (25,508/127,934) in 2022. The proportion of patients admitted with severe AHRF to ICU was 5.9% (61/1,042) in 2005 and 4.5% (5,707/127,934) in 2022.

3.5 Unadjusted Outcomes

3.5.1 All Outcomes

Below are the unadjusted outcomes for the different AHRF categories. The first table contains the outcomes for patients with AHRF compared to those without it, and the second table has the 4 categories (none, mild, moderate, severe).

Characteristic Overall1 Acute Hypoxaemic Respiratory Failure
No-AHRF (PF >300)1 AHRF (PF <300)1
Hospital Mortality 142,432 (9.1%) 39,250 (5.3%) 103,182 (12%)
ICU Mortality 93,626 (6.0%) 21,807 (3.0%) 71,819 (8.7%)
Mean ICU Length of Stay in Days (SD) 3.4 (5.7) 2.7 (4.4) 4.0 (6.5)
Median ICU Length of Stay in Days (IQR) 1.9 (1.0-3.7) 1.6 (0.9-2.9) 2.1 (1.0-4.5)
Mean Hospital Length of Stay in Days (SD) 15 (73) 14 (71) 16 (76)
Median Hospital Length of Stay in Days (IQR) 9 (5-16) 8 (5-15) 10 (6-17)
Hospital Discharge Destination


    Home 1,097,895 (70%) 549,138 (75%) 548,757 (66%)
    Nursing Home/Chronic Care/Palliative Care/Rehabilitation 142,455 (9.1%) 68,377 (9.3%) 74,078 (9.0%)
    Other Acute Care Hospital 145,532 (9.3%) 64,363 (8.8%) 81,169 (9.8%)
    Other Hospital- ICU 20,649 (1.3%) 7,324 (1.0%) 13,325 (1.6%)
    Mental Health 3,100 (0.2%) 1,721 (0.2%) 1,379 (0.2%)
    Hospital in the Home 5,609 (0.4%) 2,793 (0.4%) 2,816 (0.3%)
1 n (%); Mean (SD); Median (25%-75%)
Characteristic Overall1 Acute Respiratory Failure Category
None (PF >300)1 Mild (PF 200-300)1 Moderate (PF 100-200)1 Severe (PF < 100)1
Hospital Mortality 142,432 (9.1%) 39,250 (5.3%) 33,946 (8.0%) 46,214 (14%) 23,022 (30%)
ICU Mortality 93,626 (6.0%) 21,807 (3.0%) 20,218 (4.8%) 32,502 (10%) 19,099 (25%)
Mean ICU Length of Stay in Days (SD) 3.4 (5.7) 2.7 (4.4) 3.2 (5.5) 4.6 (6.9) 6.1 (8.7)
Median ICU Length of Stay in Days (IQR) 1.9 (1.0-3.7) 1.6 (0.9-2.9) 1.9 (1.0-3.6) 2.7 (1.3-5.1) 3.3 (1.5-7.2)
Mean Hospital Length of Stay in Days (SD) 15 (73) 14 (71) 16 (79) 17 (70) 18 (79)
Median Hospital Length of Stay in Days (IQR) 9 (5-16) 8 (5-15) 9 (6-16) 10 (6-18) 11 (5-20)
Hospital Discharge Destination




    Home 1,097,895 (70%) 549,138 (75%) 302,572 (71%) 208,950 (64%) 37,235 (48%)
    Nursing Home/Chronic Care/Palliative Care/Rehabilitation 142,455 (9.1%) 68,377 (9.3%) 39,703 (9.4%) 28,174 (8.7%) 6,201 (8.0%)
    Other Acute Care Hospital 145,532 (9.3%) 64,363 (8.8%) 40,100 (9.5%) 33,245 (10%) 7,824 (10%)
    Other Hospital- ICU 20,649 (1.3%) 7,324 (1.0%) 5,021 (1.2%) 5,916 (1.8%) 2,388 (3.1%)
    Mental Health 3,100 (0.2%) 1,721 (0.2%) 742 (0.2%) 516 (0.2%) 121 (0.2%)
    Hospital in the Home 5,609 (0.4%) 2,793 (0.4%) 1,585 (0.4%) 1,043 (0.3%) 188 (0.2%)
1 n (%); Mean (SD); Median (25%-75%)

3.5.2 Unadjusted In-Hospital Mortality and Continuous PaO2:FiO2 Ratio

The figures below represent the unadjusted outcomes.

3.6 Adjusted Outcomes

3.6.1 Primary Outcome: Conditional Probability of In-Hospital Mortality and AHRF Status

Adjusted mortality

3.6.2 Primary Outcome: Conditional Probability of In-Hospital Mortality and Continuous PaO2:FiO2 Ratio

Adjusted mortality increased as PaO2:FiO2 Ratio decreased (Adjusted ARR -3.598 (95%CI: -3.719 - -3.478)). This means that for every decrease of 100 in the PaO2:FiO2 Ratio, the conditional hospital mortality will increase by 3.598%. However, this effect is non-linear, as seen from the figure below.

3.6.4 Secondary Outcomes: Time to Death (Adjusted Analysis) Truncated at 1 Year

3.6.4.1 Cox Proportional Hazards
Characteristic HR1 95% CI1 p-value
AHRF Category


    None
    Mild 1.14 1.12, 1.15 <0.001
    Moderate 1.28 1.27, 1.30 <0.001
    Severe 1.48 1.46, 1.51 <0.001
1 HR = Hazard Ratio, CI = Confidence Interval
Characteristic HR1 95% CI1 p-value
Time Category


    2005-09
    2010-14 0.98 0.97, 1.00 0.072
    2015-19 1.06 1.04, 1.08 <0.001
    2020-22 1.10 1.08, 1.12 <0.001
1 HR = Hazard Ratio, CI = Confidence Interval
Characteristic HR1 95% CI1 p-value
Time Category


    2005-09
    2010-14 0.95 0.92, 0.98 0.004
    2015-19 1.0 0.96, 1.03 0.8
    2020-22 0.98 0.94, 1.01 0.2
1 HR = Hazard Ratio, CI = Confidence Interval
Characteristic HR1 95% CI1 p-value
Time Category


    2005-09
    2010-14 0.99 0.95, 1.03 0.5
    2015-19 1.08 1.04, 1.12 <0.001
    2020-22 1.12 1.07, 1.16 <0.001
1 HR = Hazard Ratio, CI = Confidence Interval
Characteristic HR1 95% CI1 p-value
Time Category


    2005-09
    2010-14 1.00 0.97, 1.03 >0.9
    2015-19 1.08 1.05, 1.12 <0.001
    2020-22 1.15 1.11, 1.19 <0.001
1 HR = Hazard Ratio, CI = Confidence Interval
Characteristic HR1 95% CI1 p-value
Time Category


    2005-09
    2010-14 1.03 0.98, 1.07 0.2
    2015-19 1.21 1.16, 1.26 <0.001
    2020-22 1.33 1.27, 1.40 <0.001
1 HR = Hazard Ratio, CI = Confidence Interval
3.6.4.2 Kaplan-Meier Curves

3.7 Subgroup Analysis (Adjusted Analysis)- Graphical Analysis

3.8 Subgroup Analysis (Adjusted Analysis)- Non-Graphical Analysis

3.9 Sensitivity Analysis

3.9.1 Different Severity of Illness Scores

3.9.2 Using Patients with > 12 Hours Invasive Ventilation